The broad objective of this proposal is to define the role of the maternal, fetal and neonatal liver in the postnatal regulation of fuel metabolism and nutrient assimilation by infants of diabetic mothers (IDM) and small-for-gestational-age infants (SGA). A previously used canine model during pregnancy will be employed to examine hypotheses inferred from human investigation with stable isotopic tracers and low-rate glucose infusion. Specifically, glucose:amino acid and glucose:fat interrelations will be examined under conditions of fasting and of exogenous substrate provision. Glucose turnover, gluconeogenesis, hepatic ureagenesis and diversion of glucose metabolism will be examined simultaneously in the pregnant dogs and newborn puppies with multiple radioisotopic and stable isotopic tracers. Systemic isotope dilution and product enrichment in vivo will be quantified by beta-scintillation and mass spectrometry. Intrapepatic regulations will be defined by assaying enzymatic activities and by characterizing allosteric regulation at rate-controlling sites in vivo. In order to perform such studies in the framework of an appropriate experimental design, hypotheses were generated concerning the regulation of substrates and fuels by nutrient ingestion or by fasting. In the newborn offspring of a diabetic dog, 6 arbitrarily defined fetal and neonatal "states" were linked by a hypothesis integrating hormonal control, enzymatic activation, and allosteric regulation. This approach describes the altered sequence of adaptation occurring in the IDM. Similarly, preventing maternal canine intake of foods, leads to a minor restriction of fetal growth, but causes a marked reduction in neonatal plasma glucose. Thus, metabolic regulation is greatly altered in both the canine IDM and SGA at birth.